Multiple regulatory functions of the cyclic nucleotide sensing domain of HCN channels

HCN通道环核苷酸传感结构域的多重调控功能

• 批准号: RGPIN-2016-04587
• 负责人: Young, Edgar
• 金额: $ 2.26万
• 依托单位: Simon Fraser University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=629599
• 关键词: Multiple; regulatory; functions; cyclic; nucleotide

The membranes of cells contain receptor proteins that bind natural chemical compounds (messengers) and then respond by switching their molecular structure in order to activate a specific biological function. Other proteins in the membrane switch in response to electric signals (voltage) rather than messengers. We are focusing specifically on receptors called HCN channels which are gated pores enabling transport of ions across the membrane; this gating responds both to voltage and to binding of a messenger called cyclic AMP or cAMP. My group recently discovered that although the domain responsible for cAMP-sensing is situated outside the membrane, this domain nonetheless controls the separate voltage-sensing domain embedded within the membrane. The consequence of this control is modulation of the speed at which the HCN channel pore opens in response to voltage. This is physiologically important because the cAMP messenger is generated by the body under conditions of excitation, such as the "fight-or-flight" adrenaline rush, or during epileptic seizures in some parts of the brain, where timing of a channel response is critical.

细胞膜含有受体蛋白，这些蛋白结合天然化合物(信使)，然后通过改变其分子结构来做出反应，以激活特定的生物功能。膜中的其他蛋白质响应电信号(电压)而不是信使进行开关。我们特别关注称为HCN通道的受体，这是一种门控小孔，使离子能够跨膜运输；这种门控既对电压做出反应，也对称为环磷酸腺苷或cAMP的信使的结合做出反应。我的团队最近发现，尽管负责cAMP感测的结构域位于膜外，但这个结构域仍然控制着嵌入膜内的单独的电压感应域。这种控制的结果是响应于电压调制HCN通道孔打开的速度。这在生理上很重要，因为cAMP信使是在兴奋的条件下由身体产生的，比如肾上腺素激增，或者在大脑某些部分癫痫发作时产生，其中通道反应的时机至关重要。